Dataset Information

Matching-Adjusted Indirect Comparison of Crisaborole Ointment 2% vs. Topical Calcineurin Inhibitors in the Treatment of Patients with Mild-to-Moderate Atopic Dermatitis.

ABSTRACT:

Introduction

Crisaborole topical ointment, 2%, is a nonsteroidal, topical anti-inflammatory phosphodiesterase-4 (PDE4) inhibitor that is approved for the treatment of mild-to-moderate atopic dermatitis (AD). The objective of the current analysis was to compare the efficacy of crisaborole 2% relative to pimecrolimus 1%, tacrolimus 0.03% and tacrolimus 0.1% in patients aged ≥ 2 years with mild-to-moderate AD by comparing improvement in Investigator's Static Global Assessment scores ( (ISGA scores of 0/1 indicating "clear or almost clear"). ISGA was selected as the primary efficacy outcome given the US Food and Drug Administration's recommendations on the use of ISGA for assessment of global severity in AD and to align with efficacy measurements in the crisaborole registration trials. Safety endpoints could not be analyzed due to differences in outcome definitions across studies.

Methods

Efficacy of crisaborole was evaluated using individual patient data (IPD) from two pivotal phase III randomized controlled trials (RCTs), and efficacy of comparators was evaluated using published RCTs included in a previous network meta-analysis. Vehicle controls were not comparable due to differences in ingredients and population imbalance and, therefore, an unanchored matching-adjusted indirect comparison (MAIC) was used, which reweighted IPD for crisaborole to estimate absolute response in comparator populations.

Results

The odds of achieving an improvement in ISGA score was higher with crisaborole 2% versus pimecrolimus 1% (odds ratio [OR] 2.03; 95% confidence interval [CI] 1.45-2.85; effective sample size = 627, reduced from 1021; p value < 0.001) and for crisaborole 2% versus tacrolimus 0.03% (OR 1.50; 95% CI 1.09-2.05; effective sample size = 311, reduced from 1021; p = 0.012).

Conclusion

The unanchored MAIC suggests that the odds of achieving an improvement in ISGA score is greater with crisaborole 2% than with pimecrolimus 1% or tacrolimus 0.03% in patients aged ≥ 2 years with mild-to-moderate AD. These results are consistent with findings from the previously published network meta-analysis, which used a different methodology for performing indirect treatment comparisons.

SUBMITTER: Thom H

PROVIDER: S-EPMC8776944 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionThere is a need to compare efficacy and safety profiles of crisaborole ointment, 2%, versus other topical treatments across randomized clinical trials (RCTs). We performed this review/network meta-analysis to evaluate the comparative efficacy and safety of crisaborole versus other topical pharmacologic therapies for mild-to-moderate atopic dermatitis (AD) among patients aged ≥ 2 years.MethodsSearches were conducted in MEDLINE, Embase, the Cochrane Collection Central Register of Clinical Trials, and the Database of Abstracts of Reviews of Effects using Ovid to identify English language articles reporting RCTs of topical anti-inflammatory agents in patients aged ≥ 2 years with mild-to-moderate AD published between inception and 10 March 2020. This review used a prespecified protocol with eligibility criteria for population, interventions, comparisons, outcomes, and study design. Efficacy was evaluated using the Investigator's Static Global Assessment (ISGA) of clear (0) or almost clear (1) and expressed by hazard ratios (HR) with 95% credible intervals.ResultsPatients treated with crisaborole or tacrolimus ointment, 0.1% or 0.03%, versus vehicle alone were significantly more likely to achieve ISGA 0/1 at 28-42 days, with the greatest point estimate observed for the crisaborole comparison (hazard ratio: 2.07; 95% credible interval 1.76 to - 2.36; probability HR above 1 [p better]: 100.0%). Patients were also more likely to achieve ISGA 0/1 with crisaborole than with pimecrolimus cream, 1% (HR: 1.62; 95% credible interval 1.04-2.48; p better: 98.3%). While network meta-analysis for safety was not feasible because of data limitations, crisaborole pivotal studies (AD-301/AD-302) showed crisaborole was well tolerated.ConclusionsCrisaborole was shown to be superior to vehicle and pimecrolimus and comparable to tacrolimus, 0.1% or 0.03%, with respect to ISGA 0/1 at 28-42 days in patients aged ≥ 2 years with mild-to-moderate AD. This evaluation of comparative efficacy of crisaborole further supports use of crisaborole as an effective therapeutic option in this population.

Project description:IntroductionLebrikizumab and dupilumab are monoclonal antibodies approved for treating moderate-to-severe atopic dermatitis (AD). Both have demonstrated efficacy and safety over the 16-week SOLOs and ADvocate trials. However, AD is a chronic and relapsing inflammatory disease, and the long-term maintenance of efficacy is critical for achieving disease control from the perspective of patients, physicians, and regulatory agencies. This study aims to compare the long-term efficacy and safety of lebrikizumab every 4 weeks (Q4W) and dupilumab every week or every 2 weeks (QW/Q2W) among adult patients who have achieved treatment efficacy following the induction period of 16 weeks.MethodsLebrikizumab's efficacy was assessed using individual patient data (IPD) from the ADvocate 1 and 2 monotherapy trials. Dupilumab's efficacy was evaluated using aggregate data from the adult-exclusive SOLO-CONTINUE trial. Due to the absence of a common comparator trial arm, we employed an unanchored matching-adjusted indirect comparison (MAIC), a robust methodology widely accepted by health technology assessment (HTA) agencies. This re-weights ADvocate IPD to align with SOLO-CONTINUE's prognostic factors and effect modifiers. We compared lebrikizumab's adjusted outcomes with dupilumab outcomes at week 52, focusing on 75% improvement in the Eczema Area and Severity Index from baseline (EASI-75), Investigator's Global Assessment (IGA) score of 0 or 1, and overall adverse event (AE) rates. Sensitivity analyses were conducted to test various combinations of matching variables.ResultsAdults on lebrikizumab Q4W were more likely to maintain IGA 0/1 through the 36-week maintenance period (weeks 16-52) compared with those on dupilumab QW/Q2W [risk ratio (RR) 1.334; 95% confidence interval (CI) 1.02-1.74; p = 0.035]. Both treatments demonstrated comparable efficacy in terms of EASI-75 maintenance (RR 0.937; 95% CI 0.78-1.13; p = 0.490) and similar AE rates (RR 1.052; 95% CI 0.90-1.23; p = 0.526). Sensitivity analyses substantiated these findings.ConclusionsOur findings suggest that lebrikizumab Q4W may provide equal or superior long-term maintenance of efficacy measured with EASI-75 and IGA 0/1 compared with dupilumab QW/Q2W, with the advantage of requiring less frequent doses.

Project description:Background: Crisaborole is a nonsteroidal anti-inflammatory phosphodiesterase 4 inhibitor that is approved for the treatment of patients with mild-to-moderate atopic dermatitis (AD); however, the efficacy and safety of crisaborole in patients with AD and other atopic comorbidities have not been investigated. Objective: This post hoc pooled analysis of the pivotal phase III studies (CrisADe CORE 1 and CORE 2) assessed the efficacy and safety of crisaborole versus vehicle in patients aged ≥ 2 years with mild-to-moderate AD and other atopic comorbidities. Methods: Patients with mild-to-moderate AD and a medical history of asthma, allergic rhinitis, or food allergies were identified. Efficacy assessments included the proportion of patients who achieved Investigator's Static Global Assessment (ISGA) success at day 29, ISGA clear or almost clear at day 29, and improvement in the Severity of Pruritus Scale score at week 4. Safety was assessed via treatment-emergent adverse events (TEAEs). Results: This analysis included 1522 patients (crisaborole, 1016; vehicle, 506); 26.2, 15.9, and 16.5% had a medical history of asthma, allergic rhinitis, and food allergies, respectively. The mean age was 12.2 years. A significantly greater proportion of patients treated with crisaborole achieved ISGA success at day 29 compared with patients treated with vehicle for most subgroups analyzed. Furthermore, a significantly greater proportion of patients treated with crisaborole achieved ISGA clear or almost clear at day 29 across all subgroups and demonstrated improvement in the Severity of Pruritus Scale score at week 4 versus patients treated with vehicle in most of the subgroups. Overall, most TEAEs were mild or moderate in severity; the most common treatment-related TEAE in patients with atopic comorbidities was application-site pain (crisaborole, 5.1%; vehicle, 1.7%). Conclusion: Crisaborole was efficacious and well tolerated in patients with mild-to-moderate AD and other atopic comorbidities, which suggested that crisaborole should be considered for the management of AD in this population. Clinical Trials NCT02118766 (CrisADe CORE 1) and NCT02118792 (CrisADe CORE 2), <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.clinicaltrials.gov">www.clinicaltrials.gov</ext-link>.

Project description:BackgroundTopical treatments for atopic dermatitis (AD) used reactively often fail to achieve lasting disease control; many of these therapies are associated with safety concerns that limit long-term use. Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate AD that has potential as a long-term maintenance therapy.ObjectiveThe aim was to evaluate the long-term efficacy and safety of crisaborole once daily (QD) compared to vehicle QD as a maintenance therapy to reduce the incidence of flares in patients with AD who previously responded to crisaborole twice daily (BID).MethodsCrisADe CONTROL was a randomized, double-blind, vehicle-controlled, 52-week, phase III study of patients aged ≥ 3 months with mild-to-moderate AD involving ≥ 5% treatable body surface area. Eligible patients received crisaborole BID during an open-label run-in period of up to 8 weeks. Responders were randomly assigned in the double-blind maintenance period to receive either crisaborole QD or vehicle QD. Responders were defined as patients who achieved Investigator's Static Global Assessment (ISGA) success (ISGA score of 0 [clear] or 1 [almost clear] with a ≥ 2-grade improvement) and ≥ 50% improvement in Eczema Area and Severity Index total score (EASI-50) from baseline. Patients who experienced a flare (ISGA score ≥ 2) during the double-blind maintenance period switched to crisaborole BID for up to 12 weeks. During this period, patients were assessed every 4 weeks; if the flare resolved (ISGA score ≤ 1), patients resumed their assigned treatment. The primary endpoint was flare-free maintenance until onset of the first flare. Key secondary endpoints were number of flare-free days, number of flares, and maintenance of pruritus response until onset of the first flare. The incidence of treatment-emergent adverse events was also analyzed.ResultsOverall, 497 patients entered the open-label run-in period with crisaborole BID, of which 270 patients were randomized into the 52-week double-blind maintenance period of the study. Of the 270 patients, 135 were randomly assigned to the crisaborole QD group and 135 were randomly assigned to the vehicle QD group. Median time of flare-free maintenance was longer for patients who received crisaborole versus vehicle (111 vs 30 days, respectively; p = 0.0034). The mean number of flare-free days was higher for patients who received crisaborole versus vehicle (234.0 vs 199.4 days, respectively; p = 0.0346). The mean number of flares was lower for patients who received crisaborole versus vehicle (0.95 vs 1.36, respectively; p = 0.0042). No clear trend was observed in maintenance of pruritus response between crisaborole- and vehicle-treated patients. Crisaborole was well tolerated, with no new or unexpected safety findings when used as maintenance treatment.ConclusionsCrisaborole QD was effective and well tolerated for long-term maintenance treatment and flare reduction in adult and pediatric patients with mild-to-moderate AD.Trial registrationClinicalTrials.gov, NCT04040192, 31 July 2019.